The Fick principle (cardiac output [Q(c)] = oxygen uptake [Vo(2)]/arteriovenous oxygen difference) can be used to calculate Q(c), with VO(2) frequently estimated by derived equations. To compare the accuracy of measured versus estimated VO(2), data were analyzed from 2 studies in which VO(2) at rest was measured using the Douglas bag technique. One study comprised adults with diabetes, and the other was an exercise study of healthy adults. VO(2) at rest was estimated as VO(2) (ml/min) = 125 ml/min/m(2) × body surface area (m(2)), with sensitivity analyses evaluating 2 other commonly used equations. Mean absolute difference (milliliters per minute) and ordinary least products regression were used to assess agreement between measured and estimated VO(2). Overall, mean measured versus estimated VO(2) differed significantly (307.2 ± 75.2 vs 259.9 ± 36.7 ml/min, p <0.0001), with a mean absolute difference of 52.9 ± 43.2 ml/min (p <0.0001); 20% of the estimates differed by >25% from the measured VO(2). Mean absolute difference increased from 36.7 ml/min in the lowest body mass index group (<25 kg/m(2)) to 91.7 ml/min in the highest group (≥40 kg/m(2)) (p for trend = 0.001) and was significantly higher in men than in women (65.6 vs 33.9 ml/min, p = 0.001); error was similar by median-split age (p = 0.65) and race (p = 0.34). Similar results were obtained when evaluating each of the other 2 estimating equations. Estimation of VO(2) at rest is inaccurate, especially in men and with increasing adiposity. In conclusion, when clinical hemodynamic assessment is performed, VO(2) should be measured, not estimated.